Abstract Homologous recombination (HR), which is a defense and repair mechanism, when dysregulated or elevated can lead to significant genetic changes leading to development or progression of cancer. Considerable evidence, from our laboratory and others indicates that recombination activities are both genetically modulated and inducible in mammalian cells, as they are known to be in bacteria and yeast. If homologous recombination becomes constitutively activated, such cells clearly have increased rates of subsequent mutation, which could facilitate the acquisition and progression of a tumor and/or drug resistant phenotype. This proposal will investigate an overall hypothesis that elevated HR mediates DNA instability in myeloma and may therefore contribute to acquisition, progression and development of drug resistance in MM. To evaluate this hypothesis and develop methods to overcome dysfunctionbal HR in myeloma we will follow 3 Specific Aims. To test the hypothesize that increase in HR activity is an early step in the development and progression of myeloma in Specific Aim 1, we plan To evaluate HR function in normal plasma cells, MGUS, and myeloma. To test the hypothesize that molecular mechanisms which regulate HR in normal cells are disrupted in MM, Specific Aim 2 will evaluate molecular mechanisms associated with increased HR activity and its molecular consequence in multiple myeloma. To this end we will determine 2A. the impact of recombination-related transgenic over- expression (gain of function) and manipulations on replicative potential, mutation rate, and development of drug resistance in vitro; and 2B. Determine the impact of HR inhibition on replicative potential, mutation rate, and development of drug resistance in vitro. Specific Aim 3 To develop small molecule inhibitors of HR pathway using a high-throughput, cell-based, phenotypic screen to prevent development of drug resistance and progression in myeloma. Narrative The proposed studies will improve our understanding of progression of MM and development of drug resistance and may facilitate the development of prognostic tests for disease progression and identify successful therapeutic strategies for myeloma that can also be extrapolated to number of other cancers.